. Prospective studies of 3.75 years in 4000 children <3 years old indicate primary HHV-6 illness causes a sizable healthcare burden, resulting in 20% of emergency room (ER) visits for acute illness in 6-12 month olds and one-third of febrile seizures in <2 years old evaluated in the ER. Association of HHV-6 with complicated adult disease suggests HHV-6 may result in further healthcare costs at the other end of the age spectrum. The application posits that the link spanning the age spectrum is the persistence and reactivation of HHV-6 in the interval years. The three Specific Aims are to determine: 1) whether HHV-6 persists for years in normal children, whether it reactivates, and whether risk factors are identifiable; 2) if HHV-6 is transmitted congenitally; and 3) the nature of the neurotropism of HHV-6, its pathologic and neurologic outcomes. For Aim 1, the plan is to follow 200 previously-studied children for 5 years, at which time they will be 7-12 years old, to delineate the clinical and virologic course of persistent HHV-6 and risk factors such as age, characteristics of initial infection, sites, variants, and concurrent illness. These will be correlated to the viral replicative state. Clinical assessment will involve the interviews of parents and physician, diary cards, record reviews, routine and illness visits with blood and saliva samples. Reactivation will be assessed when the child is healthy and ill by serology, detection of persistent HHV-6 by variant-specific polymerase chain reactions (PCR) and the replicative state by reverse transcriptase PCR (RT-PCR). Aim 2 will be studied in 200 normal newborns (half with and half without HHV-6 DNA in their cord blood). They will be followed up to the time of primary infection to determine the mode of transmission of asymptomatic neonatal infection and the clinical and immune effect on subsequent HHV-6 infection. The mode of transmission and later active infection will be assessed by serology, PCR, viral isolation, and RT-PCR. HHV-6 neurotropism (Aim 3) will be examined in vitro by studies of HHV-6 infection in central nervous system (CNS) tissue and clinically by the outcome measures of recurrent seizures and neurologic development. 690 children examined in the ER with their first febrile seizure (90 with seizures from HHV-6) will be followed for 2 years for recurrent seizures. A matched subgroup of 180 (90 with seizures from HHV-6 and 90 with seizures not from HHV-6) will be compared for neurologic development after 3 years by neurologic examinations and standardized neuropsychologic testing.